There is that negative argument again. Where is the evidence for this claim?
I will focus here because this appears to be the stumbling block. If we look at the DNA sequences of PRPF8 there is substantial variation yet the AA sequences show little variation. This indicates that since there is redundancy in DNA sequences that mutations are tolerated until it changes the AA sequences. When this happens purifying selection is occurring that eliminates that change from the population. Purifying selection is strong evidence of the function failing.
The high rate of purifying selection due to AA’s changing is evidence that PRPF8 is highly sensitive to AA substitution. If I take a high substitution rate of 50%(much higher than the evidence indicates) which means that half the AA’s work in every location the search space is still exceedingly high and out of the reach of a trial and error process.
Really? When I search for PRPF8 at Homologene I find that human and yeast PRPF8 only share 63% sequence identity at the protein level. How do you explain this?
Why not just substantially lower fitness?
The high rate of purifying selection due to AA’s changing is evidence that PRPF8 is highly sensitive to AA substitution. If I take a high substitution rate of 50%(much higher than the evidence indicates) which means that half the AA’s work in every location the search space is still exceedingly high and out of the reach of a trial and error process.
Why doesn’t it merely show that among those mutants there are substantially lower fitness versions, and the present sequences evolved from such lower fitness ones? How do you rule that out?
You are describing substantially lower fitness across the diversity of all living eukaryotic cells for 1.5 billion years. Can you expand on this?
It would be hard for him to expand on something that’s your mistaken understanding of what he said. There is no implication of lower fitness for 1.5 billion years.
Is PRPF8 substantially less fit in S. cerevisiae because it differs by 37% at the protein level compared to the human homolog?
Yes. You have to put ancestral sequences in the context of the organism that would have existed at the time, and the environment it lived in. What may be a lower fitness protein to a human could easily have been a well-functioning protein in one of our distant ancestors. The ancestral state was not necessarily worse at the time when it was the dominant allele in the population. I do not mean to imply that evolution is a sort of ladder with organisms becoming ever more fit.
Over time, nearly neutral mutations will accumulate even in protein coding genes. These will be nearly neutral in the context in which they occur, but once a few of them have occurred, this will have created a new mutational background for further mutations. Previously fixed nearly neutral mutations can now no longer reverse to the ancestral state, because now the context in which they would have to exist has changed, and in this new context they are no longer nearly neutral but have become deleterious. At no point in this process does the ancestor organism have to persist in a state of very low fitness.
So nearly neutral mutation A occurs, and then nearly neutral mutation B occurs later. The combination of nearly neutral mutation A and nearly neutral mutation B, means that reversal to the state before A occurred has become deleterious in the context of B. That’s it.
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You appear to be creating a tentative hypothesis on the existence of extinct organisms that may have existed between the origin of prokaryotic and eukaryotic cells. Is this right?
Do you have any thoughts on what a lower level function PRPF8 might look like?Can you make a case that the substitutability was greater than 50% or the AA count was a lot lower and grew over time.
I eventually decided that the 3D adaptive landscape imagery really caused more problems than it solves as a description. Rather, it’s a problem if you take the analogy to far. That fact is that ‘adaptive landscapes’ or surfaces are n-dimensional, not just 2D or 3D as illustrated. This means that an apparent, adaptive peak in one subset of dimensions can actually be close to other peaks in other dimensions. Thus transition states aren’t necessarily as far away from positive peaks as may be assumed in simplistic 3D representations. Also, the landscapes or surfaces are not necessarily constant but actually shift over time. Changes in the environment or even the population genetics of other members of the same species contribute to the variation the landscapes.
Just for fun, I ran a blast search on PRPF8 and downloaded the protein sequences from several species (mostly model organisms plus a couple random birds) and aligned them with MAFFT. The alignment can be viewed here.
Certainly, it’s a conserved protein, but there are literally hundreds of AA changes among different organisms.
If you can’t answer these questions with evidence then how can you claim anything about sequence space?
From the available evidence.
Then present it. Show us all of the possible amino acid sequences for PRPF8 activity as they have existed throughout the history of eukaryotes. Also, show us that species with introns could not have evolved without PRPF8.
Dave just showed the blast sequences that show preservation.
We know the spliceosome exists in most eukaryotic cells and PRPF8 is part of the U5 component and it is around 2500 AA long.
We know that PRPF8 assembly into U5 requires chaperone proteins
We know it is one of 170 proteins that make up the spliceosome
We know it currently requires the spliceosome to produce it (chicken plus egg)
We know the existence of the prokaryotic cell and its basic makeup does not include a spliceosome
We know type 2 introns don’t function properly in a eukaryotic nucleus
We can make a basic hypothesis on this evidence that the eukaryotic cell was a separate origin event or we can create a hypothesis on speculative evidence that it evolved.
I already showed you that 1 out of 3 amino acids is different between the yeast and human proteins. You have also yet to show that PRPF8 is even required for a genome that has introns.
That only shows the proteins that eukaryotes use. That doesn’t demonstrate that those are the only proteins that can fulfill that role. Again, you are committing the Sharpshooter fallacy.
Currently, yes. In the past? No. You can’t assume that what is required now was required in the past.
Dave just showed the blast sequences that show preservation.
The alignment also shows that dozens or hundreds of changes of different type and size are tolerated, apparently without compromising function.
T, I am making conclusions based on evidence. You are free to speculate all you want and that can be worth while but currently the evidence does not support your claims. The sharp shooter fallacy is not built on missing bullet holes 
I will let you have the last word.
Yes,
I have and I cited a paper previously.
I think that this is a reasonable assumption until you show positive evidence that simpler life forms are possible.
I am correcting your misapprehension about what was implied by my suggestion that an explanation for the degree of conservation seen in eukaryotic PRPF8 proteins is that lower-fitness alleles are outcompeted. Specifically, that you took me to imply that ancestral versions of the protein meant that the species at the time had lower relative fitness. I explained why that would not have to be the case.
In the larger context, I am trying to get you to explain how you rule such a scenario out.
Do you have any thoughts on what a lower level function PRPF8 might look like?
I don’t really care what it looked like, it is not my burden to resurrect the past and show it to you. YOU are the one trying to make this kind of argument:
Premise 1: PRPF8 is highly conserved. Check!
Premise 2: Sequence space for proteins of that length is 20^L, which is a very large number. Check!
Premise 3: The total number of functional sequences is less than the total sequence space. Check!
Premise 4: [ something about substitutability that you will have to express more clearly]
Premise 5-?: [Whatever premise is needed to entail, or strongly imply the conclusion]
Conclusion: Therefore it is highly doubtful, or impossible, that PRPF8 could have evolved.
So, please, fill in the missing premises.
Can you make a case that the substitutability was greater than 50% or the AA count was a lot lower and grew over time.
You’re going to have to show that “substitutability greater than 50% of the AA count”, whatever the heck that even is, is a necessary precondition for the evolution for PRPF8. This is the very thing I am trying to get you to elaborate on. Explain what that means, because I still don’t know what the fu…ntimes that even means. Once you have explained what that sentence means, we can proceed to discuss whether that requirement obtains.
They live in your gut.